Chaperoning HMGA2 protein protects stalled replication forks in stem and cancer cells.

Abstract

Maintaining genome integrity requires the accurate and complete replication of chromosomal DNA. This is of the utmost importance for embryonic stem cells (ESCs), which differentiate into cells of all lineages, including germ cells. However, endogenous and exogenous factors frequently induce stalling of replication forks in every cell cycle, which can trigger mutations and chromosomal instabilities. We show here that the oncofetal, nonhistone chromatin factor HMGA2 equips cells with a highly effective first-line defense mechanism against endonucleolytic collapse of stalled forks. This fork-stabilizing function most likely employs scaffold formation at branched DNA via multiple DNA-binding domains. Moreover, HMGA2 works independently of other human factors in two heterologous cell systems to prevent DNA strand breaks. This fork chaperone function seemingly evolved to preserve ESC genome integrity. It is hijacked by tumor (stem) cells to also guard their genomes against DNA-damaging agents widely used to treat cancer patients.

• Authors: Haojie Yu, Hong Hwa Lim, Natalia O Tjokro, Padmapriya Sathiyanathan, Suchitra Natarajan, Tian Wei Chew, Thomas Klonisch, Steven D Goodman, Uttam Surana, Peter Dröge
• Journal: Cell reports (Cell Rep) Vol. 6 Issue 4 Pg. 684-97 (Feb 27 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 24508460 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• HMGA2 Protein

Topics

• Animals
• Cell Line, Tumor
• DNA Breaks, Double-Stranded
• DNA Replication
• Embryonic Stem Cells (metabolism)
• Genomic Instability
• HMGA2 Protein (genetics, metabolism)
• Humans
• Mice
• Neoplasms (genetics, metabolism)